Embolization

ABSTRACT

Embolization, as well as related particles and methods, are described.

TECHNICAL FIELD

This invention relates to embolization, as well as related particles andmethods.

BACKGROUND

Therapeutic vascular occlusions (embolizations) are used to prevent ortreat pathological conditions in situ. Compositions including embolicparticles are used for occluding vessels in a variety of medicalapplications. Delivery of embolic particles through a catheter isdependent on size uniformity, density and compressibility of the embolicparticles.

SUMMARY

In one aspect, the invention features a method of making particles. Themethod includes combining a plurality of streams (e.g., two streams,three streams) of fluid to form drops, and forming particles from thedrops. The arithmetic mean diameter of the particles is from about tenmicrons to about 3,000 microns.

In another aspect, the invention features a method of making particles.The method includes combining a stream that includes a polymer and adifferent stream that includes a gelling precursor to form drops. Themethod also includes forming particles from the drops.

In a further aspect, the invention features a method of makingparticles. The method includes forming a plurality of streams (e.g., twostreams, three streams) of fluid from a plurality of orifices (e.g., twoorifices, three orifices), combining the plurality of streams of fluidto form drops, and forming particles from the drops. A first orifice hasa diameter of from about 50 microns to about 1000 microns (e.g., fromabout 50 microns to about 300 microns). A second orifice has an innerdiameter of from about 50 microns to about 1000 microns (e.g., fromabout 300 microns to about 600 microns) and an outer diameter of fromabout 50 microns to about 1000 microns (e.g., from about 300 microns toabout 600 microns). The outer diameter of the second orifice isdifferent from the diameter of the first orifice.

Embodiments can include one or more of the following features.

The plurality of streams of fluid can include a first stream thatincludes a first material and a second stream that includes a secondmaterial.

The first material (e.g., a polymer) can form an interior region of thedrops and the second material (e.g., a gelling precursor) can form asurface region of the drops.

The first material can include a polymer, such as, for example, apolyvinyl alcohol, a polyacrylic acid, a polymethacrylic acid, a polyvinyl sulfonate, a carboxymethyl cellulose, a hydroxyethyl cellulose, asubstituted cellulose, a polyacrylamide, a polyethylene glycol, apolyamide, a polyurea, a polyurethane, a polyester, a polyether, apolystyrene, a polysaccharide, a polylactic acid, a polyethylene, apolymethylmethacrylate, a polycaprolactone, a polyglycolic acid, apoly(lactic-co-glycolic) acid, or a combination of two or more of thesepolymers.

The second material can include a gelling precursor, such as apolysaccharide (e.g., alginate).

The first material and the second material can be immiscible.

The first material and/or the second material can include a therapeuticagent.

The viscosity of the first material can be greater than the viscosity ofthe second material. The viscosity of the second material can be greaterthan the viscosity of the first material.

The first material and/or second material can be ferromagnetic,MRI-visible (visible by magnetic resonance imaging), and/or radiopaque.

The first stream and the second stream can be concentric.

The method can further include contacting the first stream with thesecond stream (e.g., by forming a mixture of the first and secondmaterials).

The method can further include forming the first stream by flowing thefirst material through a first orifice that is defined by a nozzle.

The first material can flow through the first orifice at a rate of fromabout two milliliters per minute to about ten milliliters per minute.

The method can further include forming the second stream by flowing thesecond material through a second orifice that is defined by the nozzle.

The second material can flow through the second orifice at a rate offrom about two milliliters per minute to about 20 milliliters perminute.

The first orifice can be disposed within the second orifice. Forexample, the first orifice and the second orifice can be concentric.

The first orifice can be disposed at a vertical distance of about onemillimeter from the second orifice.

The first orifice can have a diameter of from about 50 microns to about1000 microns (e.g., from about 50 microns to about 300 microns).

The second orifice can have an inner diameter of from about 50 micronsto about 1000 microns (e.g., from about 100 microns to about 600microns, from about 300 microns to about 600 microns), and/or an outerdiameter of from about 50 microns to about 1,000 microns (e.g., fromabout 100 microns to about 600 microns, from about 300 microns to about600 microns).

The difference between the outer diameter of the second orifice and thediameter of the first orifice can be at least about 50 microns (e.g.,about 100 microns).

The method can further include adding a therapeutic agent to theparticles.

The method can further include contacting the drops with a gelling agentto form the particles.

Forming the particles can include converting the gelling precursor froma solution into a gel. The method can further include removing at leastsome of the gelling precursor from the particles.

The method can further include reacting the particles with across-linking agent.

The method can further include removing at least some of the gellingprecursor from the particles.

One or more of the particles can have a diameter of from about tenmicrons to about 3,000 microns. The particles can have an arithmeticmean diameter of from about ten microns to about 3,000 microns.

The interior region of the particles can be substantially free of thepolymer and of the gelling precursor.

The density of the polymer in the interior region of the particles canbe higher than the density of the polymer at the surface region of theparticles. The density of the gelling precursor at the surface region ofthe particles can be higher than the density of the gelling precursor inthe interior region of the particles.

The particles can contain pores. The density of pores in the interiorregion of the particles can be different from (e.g., greater than) thedensity of pores at the surface region of the particles. The averagepore size in the interior region of the particles can be different from(e.g., greater than) the average pore size at the surface region of theparticles.

The particles can be substantially non-porous.

Forming the drops can include exposing the plurality of streams to aperiodic disturbance. The periodic disturbance can be provided byvibrating the plurality of streams.

Forming the drops can include establishing an electrostatic potentialbetween the plurality of streams and a vessel configured to receive thedrops.

Embodiments can include one or more of the following advantages.

The methods can provide for a relatively effective and/or efficient wayto make particles (e.g., embolic particles), particularly particles thatinclude more than one material. For example, different orifices can beused to introduce different materials during the process of preparingthe particles. Particles including multiple materials can be desirable,for example, in embolization procedures. As an example, it can bedesirable for an embolic particle to include a therapeutic agent (e.g.,to treat a tumor). As another example, it can be desirable for anembolic particle to include a radiopaque material (e.g., to enhance theability to view the particle in the body using fluoroscopy). As afurther example, it can be desirable for an embolic particle to includea ferromagnetic material to enhance the ability to manipulate theposition of the particle in the body using a magnetic field.

The methods can provide for a relatively effective and/or efficient wayto make particles (e.g., embolic particles) of a desired size. As anexample, the streams of material that flow from different orifices canbe independently manipulated to provide a particle of a desired size. Asanother example, the viscosity of the streams can be manipulated (e.g.,reduced) to form particles of a desired size (e.g., smaller particles).

The methods can, for example, be used to form hollow particles. Whenused, for example, in an embolization procedure, hollow particles can beloaded shortly before the procedure (e.g., immediately before theprocedure), which can reduce the cost and/or complexity associated withstoring embolic compositions that include, for example, a carriersolution in addition to the particles.

Features and advantages are in the description, drawings, and claims.

DESCRIPTION OF DRAWINGS

FIG. 1A is a schematic of the manufacture of an embolic composition.

FIG. 1B is an enlarged schematic of region 1B in FIG. 1A.

FIG. 2A is a cross-sectional view of an embodiment of an apparatus forproducing particles.

FIG. 2B is an enlarged view of the apparatus of FIG. 2A, taken alongline 2B-2B.

FIG. 2C is an illustration of the production of particles by theapparatus of FIGS. 2A and 2B.

FIG. 3 is a cross-sectional view of an embodiment of a particle.

FIG. 4 is a cross-sectional view of an embodiment of a particle.

FIG. 5 is a cross-sectional view of an embodiment of a particle.

FIG. 6 is a cross-sectional view of an embodiment of a particle.

FIG. 7A is a schematic illustrating injection of an embolic compositionincluding embolic particles into a vessel, and FIG. 7B is an enlargedview of region 7B in FIG. 7A.

FIG. 8 is a cross-sectional view of an embodiment of a particle.

FIG. 9 is a cross-sectional view of an embodiment of a particle.

FIG. 10 is a cross-sectional view of an embodiment of a particle.

FIG. 11 is a cross-sectional view of an embodiment of a particle.

FIG. 12 is a cross-sectional view of an embodiment of an apparatus forproducing particles.

DETAILED DESCRIPTION

FIGS. 1A and 1B show a system 1000 for producing particles (e.g.,particles that can be used in an embolization procedure). System 1000includes a flow controller 1100, a drop generator 1200, a gelling vessel1400, a reactor vessel 1500, an optional gel dissolution chamber 1600,and a filter 1700. Drop generator 1200 includes a concentric nozzle1300. As shown in FIGS. 2A and 2B, concentric nozzle 1300 includes aninner nozzle 1330 with an inner volume 1335 and an orifice 1310 having adiameter “D.” Concentric nozzle 1300 also includes an outer nozzle 1340with an inner volume 1345 (shaded in FIG. 2A) and an orifice 1320 havingan inner diameter “ID” and an outer diameter “OD.”

Drop generator 1200 can be, for example, the Inotech Encapsulator unitIE-50R/NS (Inotech AG, Dottikon, Switzerland), or the model NISCOEncapsulation unit VAR D (NISCO Engineering, Zurich, Switzerland). Insome embodiments, concentric nozzle 1300 can be provided as anattachment to drop generator 1200. An example of a concentric nozzleattachment is the model IE-5250 attachment (available from Inotech AG).

Flow controller 1100 delivers two solutions (a polymer solution and agelling precursor solution) to a viscosity controller 1800, which heatsone or both of the solutions to achieve their respective desiredviscosities prior to delivery to drop generator 1200. In certainembodiments, before being transferred to drop generator 1200, one orboth of the solutions can be introduced to a high pressure pumpingapparatus, such as a syringe pump (e.g., model PHD4400, HarvardApparatus, Holliston, Mass.). Alternatively or additionally, dropgenerator 1200 can contain a pressure control device that applies apressure (e.g., from about 0.5 Bar to about 1.6 Bar) to one or both ofthe solutions (a pressure head) to control the rates at which thesolutions are transferred to drop generator 1200. Generally, thepressure applied to a given solution depends on the viscosity of thesolution and/or the desired flow rate of the solution.

As shown in FIG. 2C, after being delivered to drop generator 1200, astream 1350 of the polymer solution passes through volume 1335 and exitsinner nozzle 1330 via orifice 1310. A stream 1360 of the gellingprecursor solution passes through volume 1345 and exits outer nozzle1340 via orifice 1320. In some embodiments, stream 1350 and/or stream1360 can have an average diameter that is about two times the outerdiameter of the nozzle through which the stream exits. The streamsinteract as they exit the orifices. At the same time, nozzle 1300 issubjected to a periodic disturbance which results in the formation ofdrops 1370 having an interior region 1380 formed of the polymer and anexterior region 1390 formed of the gelling precursor. Drops 1370 fallinto gelling vessel 1400, where the drops are stabilized by gelformation during which the gelling precursor is converted from asolution form to a gel form. The gel-stabilized drops are thentransferred from gelling vessel 1400 to reactor vessel 1500, where thepolymer in the gel-stabilized drops is reacted, forming particles.Thereafter, the particles are filtered in filter 1700 to remove debris,and are sterilized and packaged as an embolic composition includingembolic particles. In some embodiments, the particles are transferred,prior to filtration, to gel dissolution chamber 1600. In gel dissolutionchamber 1600, the gelling precursor (which was converted to a gel) inthe particles is dissolved. After the gelling precursor is dissolved,the particles can be filtered, sterilized, and packaged, as describedabove.

In general, one or more of the parameters of the drop generation processcan be selected to form drops of a desired size. Drop size can becontrolled, for example, by controlling the diameter “D” of innerorifice 1310, the inner diameter “ID” of orifice 1320, the outerdiameter “OD” of orifice 1320, the flow rate of stream 1350, the flowrate of stream 1360, the viscosity of the polymer solution, theviscosity of the gelling precursor solution, the vibration amplitude ofconcentric nozzle 1300, and/or the vibration frequency of concentricnozzle 1300. As an example, holding other parameters constant,increasing the diameter “D” of inner orifice 1310, increasing the innerdiameter “ID” of orifice 1320, and/or increasing the outer diameter “OD”of orifice 1320 generally results in the formation of larger drops. Asanother example, holding other parameters constant, increasing the flowrate of stream 1350 and/or increasing the flow rate of stream 1360generally results in larger drops. As an additional example, holdingother parameters constant, reducing the vibration frequency ofconcentric nozzle 1300 generally results in larger drops. As a furtherexample, holding other parameters constant, increasing the viscosity ofthe polymer solution and/or increasing the viscosity of the gellingprecursor solution generally results in larger drops.

In general, the diameter “D” of inner orifice 1310 can be from about 50microns to about 1,000 microns (e.g., from about 50 microns to about 300microns, from about 100 microns to about 300 microns, from about 200microns to about 300 microns, about 200 microns, about 300 microns). Insome embodiments, diameter “D” can be about 300 microns or less (e.g.,about 200 microns or less, about 150 microns or less, about 100 micronsor less) and/or about 50 microns or more (e.g., about 100 microns ormore, about 150 microns or more, about 200 microns or more, about 250microns or more).

Orifice 1320 typically can have an outer diameter “OD” of from about 50microns to about 1,000 microns (e.g., from about 100 microns to about600 microns, from about 300 microns to about 600 microns, from about 300microns to about 500 microns, about 500 microns, about 600 microns). Incertain embodiments, orifice 1320 can have an outer diameter “OD” ofabout 100 microns or more (e.g., about 200 microns or more, about 300microns or more, about 400 microns or more, about 500 microns or more)and/or about 600 microns or less (e.g., about 500 microns or less, about400 microns or less, about 300 microns or less, about 200 microns orless).

Generally, orifice 1320 can have an inner diameter “ID” of from about 50microns to about 1,000 microns (e.g., from about 100 microns to about600 microns, from about 300 microns to about 600 microns, from about 300microns to about 500 microns, from about 400 microns to about 500microns, about 400 microns, about 500 microns). In some embodiments,orifice 1320 can have an inner diameter “ID” of about 600 microns orless (e.g., about 500 microns or less, about 400 microns or less, about300 microns or less, about 200 microns or less) and/or about 100 micronsor more (e.g., about 200 microns or more, about 300 microns or more,about 400 microns or more, about 500 microns or more).

The difference between the outer diameter “OD” of orifice 1320 and thediameter “D” of inner orifice 1310 can be at least about 50 microns(e.g., at least about 100 microns, at least about 200 microns, at leastabout 300 microns), and/or at most about 300 microns (e.g., at mostabout 200 microns, at most about 100 microns). In some embodiments, thedifference between the outer diameter “OD” of orifice 1320 and thediameter “D” of inner orifice 1310 can be about 100 microns.

In general, stream 1350 of polymer solution can flow through volume 1335of inner nozzle 1330 at a rate of from about two milliliters per minuteto about ten milliliters per minute. In some embodiments, stream 1350can flow through volume 1335 at a rate of more than about twomilliliters per minute (e.g., more than about five milliliters perminute, more than about seven milliliters per minute, more than aboutten milliliters per minute) and/or less than about ten milliliters perminute (e.g., less than about seven milliliters per minute, less thanabout five milliliters per minute, less than about two milliliters perminute).

Generally, stream 1360 of gelling precursor solution can flow throughvolume 1345 at a rate of from about two milliliters per minute to about20 milliliters per minute (e.g., from about four milliliters per minuteto about 20 milliliters per minute, from about five milliliters perminute to about 20 milliliters per minute). In some embodiments, stream1360 can flow through volume 1345 at a rate of more than about fivemilliliters per minute (e.g., more than about seven milliliters perminute, more than about ten milliliters per minute, more than about 15milliliters per minute) and/or less than about 20 milliliters per minute(e.g., less than about 15 milliliters per minute, less than about tenmilliliters per minute, less than about seven milliliters per minute).

In some embodiments, the flow rates of streams 1350 and 1360 are aboutthe same. For example, streams 1350 and 1360 can both flow throughconcentric nozzle 1300 at a rate of about five milliliters per minute.

In certain embodiments, the flow rate of stream 1350 is different fromthe flow rate of stream 1360. For example, stream 1350 can flow throughvolume 1335 at a rate of about five milliliters per minute, and stream1360 can flow through volume 1345 at a rate of about ten milliliters perminute. In some embodiments, a variation in the flow rates of streams1350 and 1360 through nozzle 1300 can enhance mixing between the streamsat their interface.

In some embodiments, stream 1360 can begin to flow through concentricnozzle 1300 before stream 1350 begins to flow through concentric nozzle1300. In certain embodiments, stream 1350 can begin to flow throughconcentric nozzle 1300 before stream 1360 begins to flow throughconcentric nozzle 1300. In such embodiments, mixing between the streamsat the interface can be relatively low.

In some embodiments, the vibration frequency of concentric nozzle 1300can be about 0.1 KHz or more (e.g., about 0.8 KHz or more, about 1.5 KHzor more, about 1.75 KHz or more, about 1.85 KHz or more, about 2.5 KHzor more, from about 0.1 KHz to about 0.8 KHz).

In certain embodiments, the vibration amplitude of concentric nozzle1300 is larger than the width of the drops 1370. In some embodiments,drop generator 1200 has a variable vibration amplitude setting, suchthat an operator can adjust the amplitude of the concentric nozzlevibration. In such embodiments, the vibration amplitude can be set, forexample, at between about 80 percent and about 100 percent of themaximum setting.

In general, the viscosity of the polymer solution can be from about tencentipoise to about 50 centipoise (e.g., about 25 centipoise).Alternatively or additionally, the viscosity of the gelling precursorsolution can be from about ten centipoise to about 100 centipoise (e.g.,about 50 centipoise). In some embodiments, a solution with a viscosityof about 50 centipoise can produce drops with a diameter of from about100 microns to about 1200 microns. Typically, the viscosity of aconcentric stream of two different materials can be lower than theviscosity of a mixed stream of the two different materials. Generally, alower viscosity solution can flow through a smaller orifice than ahigher viscosity solution, and thus can produce smaller drops than thehigher viscosity solution.

As described above, viscosity controller 1800 can be used in the dropformation process to control the viscosity of the polymer solution andthe gelling precursor solution. Viscosity controller 1800 is a heatexchanger that circulates water at a predetermined temperature about theflow tubing between the pump and drop generator 1200. The polymersolution and the gelling precursor solution flow into viscositycontroller 1800, where the solutions are heated so that theirviscosities are lowered to a desired level. Alternatively oradditionally, vessels containing the solutions can be disposed in aheated fluid bath (e.g., a heated water bath) to heat the solutions. Insome embodiments (e.g., when the system does not contain viscositycontroller 1800), flow controller 1100 and/or drop generator 1200 can beplaced in a temperature-controlled chamber (e.g. an oven, a heat tapewrap) to the heat polymer solution and the gelling precursor solution.In general, for a given solution, the lower the desired viscosity of thesolution, the higher the temperature to which the solution is heated.For example, in some embodiments, a solution with a desired viscosity ofabout 100 centipoise can be heated to a temperature of about 65° C.,while a solution with a desired viscosity of about 50 centipoise can beheated to a temperature of about 75° C. In certain embodiments,viscosity controller 1800 can heat the solutions to allow for flowthrough an orifice of a particular size. Generally, for a givensolution, the smaller the size of the nozzle orifice, the higher thetemperature to which the solution is heated. For example, in someembodiments, a solution that flows through an orifice with a diameter ofabout 200 microns can be heated to a temperature of about 65° C., whilethe same solution, when flowing through an orifice with a diameter ofabout 100 microns, can be heated to a temperature of about 75° C.

The viscosity of the polymer solution and/or the gelling precursorsolution can alternatively or additionally be adjusted by changing theconcentration of the polymer and/or gelling precursor in the solution.In general, as the concentration of polymer and/or gelling precursor inthe solution increases, the viscosity of the solution increases. If, forexample, the desired viscosity of a polyvinyl alcohol solution is about25 centipoise, then the solution can be prepared to have a concentrationof about eight percent polyvinyl alcohol. If, for example, the desiredviscosity of an alginate solution is about 50 centipoise, then thesolution can be prepared to have a concentration of about two percentalginate.

The pressure applied to the gelling precursor solution and/or thepolymer solution in the drop formation process can be selected, forexample, based on the desired size of the drops and/or the viscositiesof the solutions. In general, for a given solution, as the size of thenozzle orifice decreases (e.g., to produce smaller particles), thepressure applied to the solution increases. For example, a pressure ofabout 0.5 Bar can be applied to a solution with a viscosity of about 50centipoise that flows through an orifice with a diameter of about 300microns. A pressure of about 0.8 Bar can be applied to the same solutionwith the same viscosity when the solution flows through an orifice witha diameter of about 200 microns. Generally, for a given solution flowingthrough an orifice of a given diameter, as the viscosity of the solutiondecreases, the pressure that is applied to the solution decreases. Forexample, a pressure of about 0.8 Bar can be applied to a solution with aviscosity of about 50 centipoise when the solution flows through anorifice with a diameter of about 200 microns. A pressure of about 0.5Bar can be applied to the same solution when the solution flows throughthe same orifice, but has a different viscosity (e.g., about 25centipoise).

In general, the distance between gelling vessel 1400 and inner orifice1310 and/or orifice 1320 is selected so that the drops are separatedbefore reaching vessel 1400. In some embodiments, the distance frominner orifice 1310 and/or orifice 1320 to the mixture contained ingelling vessel 1400 is from about five inches to about eight inches(e.g., from about five inches to about six inches).

In general, the polymer solution and gelling precursor solution can beformed according to any of a number of different methods. In someembodiments, the polymer solution and/or gelling precursor solution canbe formed by dissolving one or more polymers and/or gelling precursorsin water prior to use in drop generator 1200. The polymer can, forexample, be dissolved in water by heating (e.g., above about 70° C. ormore, about 121° C.). The gelling precursor can, for example, bedissolved in water at room temperature. In certain embodiments, thepolymer solution and/or the gelling precursor solution can be formed bymixing water with one or more polymers and/or gelling precursors andheating the mixture in an autoclave. Heat can alternatively oradditionally be applied to a mixture of water and one or more polymersand/or gelling precursors by, for example, microwave application. Insome embodiments, a homogenizer (e.g., in combination with microwaveapplication) can be used to mix the water with the polymer(s) and/orgelling precursor(s).

Generally, the polymer or polymers used in the polymer solution, and thegelling precursor or precursors used in the gelling precursor solution,are biocompatible.

Examples of polymers include polyvinyl alcohols, polyacrylic acids,polymethacrylic acids, poly vinyl sulfonates, carboxymethyl celluloses,hydroxyethyl celluloses, substituted celluloses, polyacrylamides,polyethylene glycols, polyamides, polyureas, polyurethanes, polyesters,polyethers, polystyrenes, polysaccharides, polylactic acids,polyethylenes, polymethylmethacrylates, polycaprolactones, polyglycolicacids, poly(lactic-co-glycolic) acids (e.g., poly(d-lactic-co-glycolic)acids) and copolymers or mixtures thereof. A preferred polymer ispolyvinyl alcohol (PVA). The polyvinyl alcohol, in particular, istypically hydrolyzed in the range of from about 80 percent to about 99percent. The weight average molecular weight of the base polymer can be,for example, in the range of from about 9000 to about 186,000 (e.g.,from about 85,000 to about 146,000, from about 89,000 to about 98,000).

Examples of gelling precursors include alginates, alginate salts,xanthan gums, natural gum, agar, agarose, chitosan, carrageenan,fucoidan, furcellaran, laminaran, hypnea, eucheuma, gum arabic, gumghatti, gum karaya, gum tragacanth, hyalauronic acid, locust beam gum,arabinogalactan, pectin, amylopectin, other water solublepolysaccharides and other ionically cross-linkable polymers. Aparticular gelling precursor is sodium alginate. A preferred sodiumalginate is high guluronic acid, stem-derived alginate (e.g., about 50percent or more, about 60 percent or more guluronic acid) with a lowviscosity (e.g., from about 20 centipoise to about 80 centipoise at 20°C.), which produces a high tensile, robust gel.

The mixture contained in gelling vessel 1400 includes a gelling agentwhich interacts with the gelling precursor to stabilize drops by forminga stable gel. Suitable gelling agents include, for example, a chargedpolymer (e.g., polyacrylic acid), or a divalent cation such as alkalimetal salt, alkaline earth metal salt or a transition metal salt thatcan ionically cross-link with the gelling precursor. An inorganic salt,for example, a calcium, barium, zinc or magnesium salt can be used as agelling agent. In embodiments, particularly those using an alginategelling precursor, a suitable gelling agent is calcium chloride. Thecalcium cations have an affinity for carboxylic groups in the gellingprecursor. The cations complex with carboxylic groups in the gellingprecursor, resulting in encapsulation of the polymer by the gellingprecursor.

Without wishing to be bound by theory, it is believed that in someembodiments (e.g., when forming particles having a diameter of about 500microns or less), it can be desirable to reduce the surface tension ofthe mixture contained in gelling vessel 1400. This can be achieved, forexample, by heating the mixture in gelling vessel 1400 (e.g., to atemperature greater than room temperature, such as a temperature ofabout 30° C. or more (e.g., a temperature of about 80° C. or more)), bybubbling a gas (e.g., air, nitrogen, argon, krypton, helium, neon)through the mixture contained in gelling vessel 1400, by stirring (e.g.,via a magnetic stirrer) the mixture contained in gelling vessel 1400, byincluding a surfactant in the mixture containing the gelling agent,and/or by forming a mist containing the gelling agent above the mixturecontained in gelling vessel 1400 (e.g., to reduce the formation of tailsand/or enhance the sphericity of the particles).

As noted above, following drop stabilization, the gelling solution canbe decanted from the solid drops, or the solid drops can be removed fromthe gelling solution by sieving. The solid drops are then transferred toreactor vessel 1500, where the polymer in the solid drops is reacted(e.g., cross-linked) to produce particles.

Reactor vessel 1500 contains an agent that chemically reacts with thepolymer to cause cross-linking between polymer chains and/or within apolymer chain. For example, in embodiments in which the polymer ispolyvinyl alcohol, vessel 1500 can include one or more aldehydes, suchas formaldehyde, glyoxal, benzaldehyde, aterephthalaldehyde,succinaldehyde and glutaraldehyde for the acetalization of polyvinylalcohol. Vessel 1500 also can include an acid, for example, strong acidssuch as sulfuric acid, hydrochloric acid, nitric acid and weak acidssuch as acetic acid, formic acid and phosphoric acid. In embodiments,the reaction is primarily a 1,3-acetalization:

This intra-chain acetalization reaction can be carried out withrelatively low probability of inter-chain cross-linking, as described inJohn G. Pritchard, “Poly(Vinyl Alcohol) Basic Properties and Uses(Polymer Monograph, vol. 4) (see p. 93-97), Gordon and Breach, SciencePublishers Ltd., London, 1970, which is incorporated herein byreference. Because the reaction proceeds in a random fashion, some OHgroups along a polymer chain might not react with adjacent groups andmay remain unconverted.

Adjusting for the amounts of aldehyde and acid used, reaction time andreaction temperature can control the degree of acetalization. Inembodiments, the reaction time is from about five minutes to about onehour (e.g., from about 10 minutes to about 40 minutes, about 20minutes). The reaction temperature can be, for example, from about 25°C. to about 150° C. (e.g., from about 75° C. to about 130° C., about 65°C.). Reactor vessel 1500 can be placed in a water bath fitted with anorbital motion mixer. The particles are washed several times withdeionized water to remove residual acidic solution.

FIG. 3 shows a particle 10 that can be formed by the process noted above(without dissolving the gelling precursor). Particle 10 includes aninterior region 12 formed of the polymer and an exterior region 16formed of the gelling precursor (which is in a gelled state as explainedabove).

In general, particle 10 can have a diameter of from about ten microns toabout 3,000 microns (e.g., from about 40 microns to about 2,000 microns;from about 100 microns to about 700 microns; from about 500 microns toabout 700 microns; from about 100 microns to about 500 microns; fromabout 100 microns to about 300 microns; from about 300 microns to about500 microns; from about 500 microns to about 1,200 microns; from about500 microns to about 700 microns; from about 700 microns to about 900microns; from about 900 microns to about 1,200 microns). In someembodiments, particle 10 can have a diameter of about 3,000 microns orless (e.g., about 2,500 microns or less; about 2,000 microns or less;about 1,500 microns or less; about 1,200 microns or less; about 1,000microns or less; about 900 microns or less; about 700 microns or less;about 500 microns or less; about 400 microns or less; about 300 micronsor less; about 100 microns or less) and/or about ten microns or more(e.g., about 100 microns or more; about 300 microns or more; about 400microns or more; about 500 microns or more; about 700 microns or more;about 900 microns or more; about 1,000 microns or more; about 1,200microns or more; about 1,500 microns or more; about 2,000 microns ormore; about 2,500 microns or more).

In certain embodiments, particle 10 can have a sphericity of about 0.8or more (e.g., about 0.85 or more, about 0.9 or more, about 0.95 ormore, about 0.97 or more). The sphericity of a particle can bedetermined using a Beckman Coulter RapidVUE Image Analyzer version 2.06(Beckman Coulter, Miami, Fla.). Briefly, the RapidVUE takes an image ofcontinuous-tone (gray-scale) form and converts it to a digital formthrough the process of sampling and quantization. The system softwareidentifies and measures particles in an image in the form of a fiber,rod or sphere. The sphericity of a particle, which is computed as Da/Dp(where Da=√(4A/π); Dp=P/π; A=pixel area; P=pixel perimeter), is a valuefrom zero to one, with one representing a perfect circle.

As noted above, in some embodiments, the gelling precursor (in a gelledstate) is removed from particles 10 (e.g., by an ion exchange reaction),forming particles 100, shown in FIG. 4. Particles 100 include thepolymer but are substantially free of the gelling precursor. In someembodiments in which the gelling precursor is formed of sodium alginate,the sodium alginate is removed by ion exchange with a solution of sodiumhexa-metaphosphate (EM Science). The solution can include, for example,ethylenediaminetetracetic acid (EDTA), citric acid, other acids, andphosphates. The concentration of the sodium hexa-metaphosphate can be,for example, from about one weight percent to about 20 weight percent(e.g., from about one weight percent to about ten weight percent, aboutfive weight percent) in deionized water. Residual gelling precursor(e.g., sodium alginate) can be measured by assay (e.g., for thedetection of uronic acids in, for example, alginates containingmannuronic and guluronic acid residues). A suitable assay includesrinsing the particles with sodium tetraborate in sulfuric acid solutionto extract alginate, combining the extract with metahydroxydiphenylcolormetric reagent, and determining concentration by UV/VISspectroscopy. Testing can be carried out by alginate suppliers such asFMC Biopolymer, Oslo, Norway. Residual alginate may be present in therange of, for example, from about 20 weight percent to about 35 weightpercent prior to rinsing, and in the range of from about 0.01 weightpercent to about 0.5 weight percent (e.g., from about 0.1 weight percentto about 0.3 weight percent, about 0.18 weight percent) in the particlesafter rinsing for 30 minutes in water at about 23° C.

In some embodiments, and as shown in FIGS. 5 and 6, the gellingprecursor can be removed from a particle to form a smaller particle witha rough surface. FIG. 5 shows a particle 200 with an interior region 210that includes a polymer and an exterior region 230 that includes agelling precursor. A boundary 250 between the gelling precursor and thepolymer is not well-defined. Such a boundary can be formed, for example,when there is some mixing between the gelling precursor solution and thepolymer solution at the interface between the two solutions during theformation of particle 200. When the gelling precursor is removed fromparticle 200, a particle 300 having a rough surface 310, shown in FIG.6, can result. Particle 300 is formed substantially of the polymer andis substantially free of the gelling precursor.

As noted above, after either cross-linking or removal of the gellingprecursor, the particles formed using concentric nozzle 1300 arefiltered through filter 1700 to remove residual debris. Particles offrom about 100 microns to about 300 microns can filtered through a sieveof about 710 microns and then a sieve of about 300 microns. Theparticles can then be collected on a sieve of about 20 microns.Particles of from about 300 to about 500 microns can filtered through asieve of about 710 microns and then a sieve of about 500 microns. Theparticles can then be collected on a sieve of about 100 microns.Particles of from about 500 to about 700 microns can be filtered througha sieve of about 1000 microns, then filtered through a sieve of about710 microns, and then a sieve of about 300 microns. The particles canthen be collected in a catch pan. Particles of from about 700 to about900 microns can be filtered through a sieve of 1000 microns and then asieve of 500 microns. The particles can then be collected in a catchpan. Particles of from about 900 to about 1200 microns can filteredthrough a sieve of 1180 microns and then a sieve of 710 microns. Theparticles can then be collected in a catch pan. Other size sieves can beused if desired.

The particles are then packaged. Typically, from about one milliliter toabout five milliliters of particles are packaged in from about fivemilliliters to about ten milliliters of saline. The filtered particlesthen are typically sterilized by a low temperature technique, such ase-beam irradiation. In embodiments, electron beam irradiation can beused to pharmaceutically sterilize the particles (e.g., to reducebioburden). In e-beam sterilization, an electron beam is acceleratedusing magnetic and electric fields, and focused into a beam of energy.The resultant energy beam can be scanned by means of an electromagnet toproduce a “curtain” of accelerated electrons. The accelerated electronbeam penetrates the collection of particles, destroying bacteria andmold to sterilize and reduce the bioburden in the particles. Electronbeam sterilization can be carried out by sterilization vendors such asTitan Scan, Lima, Ohio.

In some embodiments, multiple particles are combined with a carrierfluid (e.g., a pharmaceutically acceptable carrier, such as a salinesolution, a contrast agent, or both) to form an embolic composition. Ingeneral, the density of the particles (e.g., as measured in grams ofmaterial per unit volume) is such that they can be readily suspended inthe carrier fluid and remain suspended during delivery. In someembodiments, the density of a particle is from about 1.1 grams per cubiccentimeter to about 1.4 grams per cubic centimeter. As an example, forsuspension in a saline-contrast solution, the density can be from about1.2 grams per cubic centimeter to about 1.3 grams per cubic centimeter.

Embolic compositions can be used in, for example, neural, pulmonary,and/or AAA (abdominal aortic aneurysm) applications. The compositionscan be used in the treatment of, for example, fibroids, tumors, internalbleeding, arteriovenous malformations (AVMs), and/or hypervasculartumors. The compositions can be used as, for example, fillers foraneurysm sacs, AAA sac (Type II endoleaks), endoleak sealants, arterialsealants, and/or puncture sealants, and/or can be used to provideocclusion of other lumens such as fallopian tubes. Fibroids can includeuterine fibroids which grow within the uterine wall (intramural type),on the outside of the uterus (subserosal type), inside the uterinecavity (submucosal type), between the layers of broad ligamentsupporting the uterus (interligamentous type), attached to another organ(parasitic type), or on a mushroom-like stalk (pedunculated type).Internal bleeding includes gastrointestinal, urinary, renal and varicosebleeding. AVMs are for example, abnormal collections of blood vessels,e.g. in the brain, which shunt blood from a high pressure artery to alow pressure vein, resulting in hypoxia and malnutrition of thoseregions from which the blood is diverted. In some embodiments, acomposition containing the particles can be used to prophylacticallytreat a condition.

The magnitude of a dose of an embolic composition can vary based on thenature, location and severity of the condition to be treated, as well asthe route of administration. A physician treating the condition, diseaseor disorder can determine an effective amount of embolic composition. Aneffective amount of embolic composition refers to the amount sufficientto result in amelioration of symptoms or a prolongation of survival ofthe subject. The embolic compositions can be administered aspharmaceutically acceptable compositions to a subject in anytherapeutically acceptable dosage, including those administered to asubject intravenously, subcutaneously, percutaneously, intratrachealy,intramuscularly, intramucosaly, intracutaneously, intra-articularly,orally or parenterally.

An embolic composition can include a mixture of particles (e.g.,particles that include different types of therapeutic agents), or caninclude particles that are all of the same type. In some embodiments, anembolic composition can be prepared with a calibrated concentration ofparticles for ease of delivery by a physician. A physician can select anembolic composition of a particular concentration based on, for example,the type of embolization procedure to be performed. In certainembodiments, a physician can use an embolic composition with arelatively high concentration of particles during one part of anembolization procedure, and an embolic composition with a relatively lowconcentration of particles during another part of the embolizationprocedure.

Suspensions of particles in saline solution can be prepared to remainstable (e.g., to remain suspended in solution and not settle and/orfloat) over a desired period of time. A suspension of particles can bestable, for example, for from about one minute to about 20 minutes (e.g.from about one minute to about ten minutes, from about two minutes toabout seven minutes, from about three minutes to about six minutes).

In some embodiments, particles can be suspended in a physiologicalsolution by matching the density of the solution to the density of theparticles. In certain embodiments, the particles and/or thephysiological solution can have a density of from about one gram percubic centimeter to about 1.5 grams per cubic centimeter (e.g., fromabout 1.2 grams per cubic centimeter to about 1.4 grams per cubiccentimeter, from about 1.2 grams per cubic centimeter to about 1.3 gramsper cubic centimeter).

FIGS. 7A and 7B show an embolization procedure in which an emboliccomposition including embolic particles 400 and a carrier fluid isinjected into a vessel through an instrument such as a catheter 410.Catheter 410 is connected to a syringe barrel 420 with a plunger 430.The embolic composition is loaded into syringe barrel 420, and catheter410 is inserted, for example, into a femoral artery 440 of a patient.Plunger 430 of syringe barrel 420 is then compressed to deliver theembolic composition through catheter 410 into a lumen 450 of a uterineartery 460 that leads to a fibroid 470 located in the uterus of thepatient. The embolic composition can, for example, occlude uterineartery 460.

As shown in FIG. 7B, uterine artery 460 is subdivided into smalleruterine vessels 480 (e.g., having a diameter of about two millimeters orless) which feed fibroid 470. Particles 400 in the embolic compositionpartially or totally fill the lumen of uterine artery 460, eitherpartially or completely occluding the lumen of the uterine artery 460that feeds uterine fibroid 470.

In some embodiments, among the particles delivered to a subject in anembolic composition, the majority (e.g., about 50 percent or more, about60 percent or more, about 70 percent or more, about 80 percent or more,about 90 percent or more) of the particles can have a diameter of about3,000 microns or less (e.g., about 2,500 microns or less; about 2,000microns or less; about 1,500 microns or less; about 1,200 microns orless; about 900 microns or less; about 700 microns or less; about 500microns or less; about 400 microns or less; about 300 microns or less;about 100 microns or less) and/or about ten microns or more (e.g., about100 microns or more; about 300 microns or more; about 400 microns ormore; about 500 microns or more; about 700 microns or more; about 900microns or more; about 1,200 microns or more; about 1,500 microns ormore; about 2,000 microns or more; about 2,500 microns or more).

In certain embodiments, the particles delivered to a subject in anembolic composition can have an arithmetic mean diameter of from aboutten microns to about 3,000 microns. In some embodiments, the particlescan have an arithmetic mean diameter of about 3,000 microns or less(e.g., about 2,500 microns or less; about 2,000 microns or less; about1,500 microns or less; about 1,200 microns or less; about 900 microns orless; about 700 microns or less; about 500 microns or less; about 400microns or less; about 300 microns or less; about 100 microns or less)and/or about ten microns or more (e.g., about 100 microns or more; about300 microns or more; about 400 microns or more; about 500 microns ormore; about 700 microns or more; about 900 microns or more; about 1,200microns or more; about 1,500 microns or more; about 2,000 microns ormore; about 2,500 microns or more). Exemplary ranges for the arithmeticmean diameter of particles delivered to a subject include from about 100microns to about 300 microns; from about 300 microns to about 500microns; from about 500 microns to about 700 microns; and from about 900microns to about 1,200 microns. In general, the particles delivered to asubject in an embolic composition can have an arithmetic mean diameterin approximately the middle of the range of the diameters of theindividual particles, and a variance of about 20 percent or less (e.g.about 15 percent or less, about ten percent or less).

In some embodiments, the arithmetic mean diameter of the particlesdelivered to a subject in an embolic composition can vary depending uponthe particular condition to be treated. As an example, in embodiments inwhich the particles in an embolic composition are used to treat a livertumor, the particles delivered to the subject can have an arithmeticmean diameter of about 500 microns or less (e.g., from about 100 micronsto about 300 microns; from about 300 microns to about 500 microns). Asanother example, in embodiments in which the particles in an emboliccomposition are used to treat a uterine fibroid, the particles deliveredto the subject in an embolic composition can have an arithmetic meandiameter of about 1,200 microns or less (e.g., from about 500 microns toabout 700 microns; from about 700 microns to about 900 microns; fromabout 900 microns to about 1,200 microns).

The arithmetic mean diameter of a group of particles can be determinedusing a Beckman Coulter RapidVUE Image Analyzer version 2.06 (BeckmanCoulter, Miami, Fla.), described above. The arithmetic mean diameter ofa group of particles (e.g., in a composition) can be determined bydividing the sum of the diameters of all of the particles in the groupby the number of particles in the group.

In certain embodiments, the sphericity of a particle after compressionin a catheter (e.g., after compression to about 50 percent or more ofthe cross-sectional area of the particle) can be about 0.8 or more(e.g., about 0.85 or more, about 0.9 or more, about 0.95 or more, about0.97 or more). The particle can be, for example, manually compressed,essentially flattened, while wet to about 50 percent or less of itsoriginal diameter and then, upon exposure to fluid, regain a sphericityof about 0.8 or more (e.g., about 0.85 or more, about 0.9 or more, about0.95 or more, about 0.97 or more).

While substantially spherical particles have been shown, in someembodiments a concentric nozzle can be used to make one or morenon-spherical particles. For example, a concentric nozzle can be used tomake crescent-shaped particles, as shown in FIGS. 8 and 9. FIG. 8 showsa precursor particle 800, formed by a concentric nozzle. Precursorparticle 800 has a crescent-shaped interior region 810 that includes apolymer, and an exterior region 830 that includes a gelling precursor.Exterior region 830 can be removed (e.g., by exposing precursor particle800 to a gel dissolution chamber) to produce crescent-shaped particle900, shown in FIG. 9, which is formed substantially of polymer. Whileprecursor particles with interior crescent-shaped regions have beenshown, in some embodiments precursor particles with exteriorcrescent-shaped regions can be formed. In certain embodiments, precursorparticles with crescent-shaped regions can be formed by using a firstmaterial and a second material that has a much greater (e.g., by 50centipoise) viscosity than the first material. In some embodiments,precursor particles with crescent-shaped regions can be formed by usinga higher flow rate (e.g., about 15 milliliters per minute) for thestream that flows through one nozzle (e.g., the outer nozzle) of aconcentric nozzle and a lower flow rate (e.g., about seven millilitersper minute) for the stream that flows through another nozzle (e.g., theinner nozzle) of the concentric nozzle.

Other Embodiments

While certain embodiments have been described, the invention is not solimited.

As an example, while embodiments have been described in which a polymersolution flows through the inner nozzle and a gelling precursor solutionflows through the outer nozzle, in some embodiments, a polymer solutionflows through the outer nozzle and a gelling precursor solution flowsthrough the inner nozzle. If the gelling precursor is not dissolved, theresulting particles can have, for example, an interior region formed ofgelling precursor (in a gelled state) and an exterior region formed ofpolymer. FIG. 10 shows such a particle 500 having an interior region 510formed of gelling precursor (in a gelled state) and an exterior region530 formed of polymer. If the gelling precursor is dissolved, theresulting particles can have, for example, a hollow interior and anexterior region formed of polymer. FIG. 11 shows such a particle 600having a hollow interior region 610 and exterior region 530 (formed ofpolymer). In certain embodiments, particle 600 can be used to deliverone or more agents (e.g., therapeutic agents) into the body (seediscussion below). For example, the agent(s) can be injected into hollowinterior region 610 of particle 600 prior to delivery.

As another example, while embodiments of a concentric nozzle having twonozzles have been described, other embodiments are possible. In general,a concentric nozzle can have more than two (e.g., three, four, five,six, seven, eight, nine, ten) nozzles. Typically, each nozzle in aconcentric nozzle has a stream of a particular material that flowstherethrough. In some embodiments, however, a stream of a particularmaterial may flow through more than one nozzle.

As a further example, in some embodiments drops may be formed withoutvibrating the concentric nozzle. In certain embodiments, drops can beformed by establishing an electrostatic potential between concentricnozzle 1300 and gelling vessel 1400 so that the streams exitingconcentric nozzle 1300 are pulled toward gelling vessel 1400, therebyforming drops. An electrostatic potential can be established, forexample, by charging concentric nozzle 1300 and charging gelling vessel1400 with the opposite charge. For example, concentric nozzle 1300 canbe negatively charged and gelling vessel 1400 can be positively charged.An example of a commercially available drop generator that forms dropsby the use of an electrostatic potential is the NISCO Encapsulation unitVAR V1 (NISCO Engineering, Zurich, Switzerland). In some embodiments,drops can be formed by using a drop generator that employs both anelectrostatic potential and a periodic disturbance (e.g., vibration ofthe concentric nozzle). In certain embodiments, drops can be formed bymechanically breaking the streams exiting concentric nozzle 1300 intodrops 1370 (e.g., by a jet cutter). Optionally, drops may be formed byusing a combination of vibration techniques and/or mechanical break-uptechniques and/or electrostatic techniques.

As an additional example, in some embodiments, drop generator 1200 cancharge drops 1370 after formation and prior to contact with the gellingagent, such that mutual repulsion between drops 1370 prevents dropaggregation as the drops travel from drop generator 1200 to gellingvessel 1400. Charging may be achieved, for example, by an electrostaticcharging device such as a charged ring positioned downstream ofconcentric nozzle 1300.

As an additional example, while the formation of crescent-shapedparticles has been described, in some embodiments, a drop generationprocess can be performed in a way that limits the likelihood of formingcrescent-shaped particles and/or particles with crescent-shaped regions.For example, a polymer solution that flows through the volume defined byan inner nozzle of a concentric nozzle can include a relatively smallconcentration (e.g., up to about one percent) of a gelling agent (e.g.,calcium ions). The presence of gelling agent in the polymer solution canreduce the likelihood of formation of particles with crescent-shapedregions (such as precursor particle 800 in FIG. 8). While not beingbound by theory, it is believed that the gelling agent in the polymersolution can cause the polymer to begin to gel prior to the formation ofa drop containing the polymer. If, for example, a gelling precursorsolution is flowing through the outer nozzle of the concentric nozzle,then when the drop that is formed contacts gelling agent, both theinterior region and the exterior region of the drop may gel. Thus, thedrop can be gelling from both the inside out and the outside in. Suchgelling may result in particles in which both the interior regions andthe exterior regions are substantially spherical.

As another example, in certain embodiments, one or more of the materialsthat flow through one or more of the orifices in a concentric nozzle canbe a therapeutic agent (e.g., drug), such that particles formed by theconcentric nozzle incorporate the therapeutic agent(s). Alternatively oradditionally, one or more therapeutic agents can be added to theparticles after forming the particles. In some embodiments, atherapeutic agent can be added to a particle by, e.g., injection of thetherapeutic agent into the particle and/or by soaking the particle inthe therapeutic agent. Therapeutic agents include agents that arenegatively charged, positively charged, amphoteric, or neutral.Therapeutic agents can be, for example, materials that are biologicallyactive to treat physiological conditions; pharmaceutically activecompounds; gene therapies; nucleic acids with and without carriervectors; oligonucleotides; gene/vector systems; DNA chimeras; compactingagents (e.g., DNA compacting agents); viruses; polymers; hyaluronicacid; proteins (e.g., enzymes such as ribozymes); cells (of humanorigin, from an animal source, or genetically engineered); stem cells;immunologic species; nonsteroidal anti-inflammatory medications; oralcontraceptives; progestins; gonadotrophin-releasing hormone agonists;chemotherapeutic agents; and radioactive species (e.g., radioisotopes,radioactive molecules). Non-limiting examples of therapeutic agentsinclude anti-thrombogenic agents; antioxidants; angiogenic andanti-angiogenic agents and factors; anti-proliferative agents (e.g.,agents capable of blocking smooth muscle cell proliferation);anti-inflammatory agents; calcium entry blockers;antineoplastic/antiproliferative/anti-mitotic agents (e.g., paclitaxel,doxorubicin, cisplatin); antimicrobials; anesthetic agents;anti-coagulants; vascular cell growth promoters; vascular cell growthinhibitors; cholesterol-lowering agents; vasodilating agents; agentswhich interfere with endogenous vasoactive mechanisms; and survivalgenes which protect against cell death. In some embodiments, release ofa therapeutic agent from a particle can be triggered by one or morefactors. For example, release of a therapeutic agent can be triggered bypH, ions, and/or temperature. Therapeutic agents are described, forexample, in co-pending U.S. Patent Application Publication No. US2004/0076582 A1, published on Apr. 22, 2004, which is incorporatedherein by reference.

As an additional example, in some embodiments, one or more of thematerials that flows through one or more of the orifices in a concentricnozzle can be a diagnostic agent (e.g., a radiopaque material, amaterial that is visible by magnetic resonance imaging (an MRI-visiblematerial), an ultrasound contrast agent). In some embodiments, one ormore of the materials used in concentric nozzle can be a ferromagneticmaterial. Alternatively or additionally, one or more diagnostic agentsand/or ferromagnetic materials can be added to the particles afterforming the particles. In some embodiments, a diagnostic agent and/orferromagnetic material can be added to a particle by, e.g., injection ofthe diagnostic agent and/or ferromagnetic material into the particleand/or by soaking the particle in the diagnostic agent and/orferromagnetic material. Diagnostic agents and ferromagnetic materialsare described in U.S. Patent Application Publication No. US 2004/0101564A1, published on May 27, 2004, and entitled “Embolization”, which isincorporated herein by reference.

As another example, in certain embodiments, one or more of the materialsthat flow through one or more of the orifices in a concentric nozzle canbe a shape memory material, which is capable of being configured toremember (e.g., to change to) a predetermined configuration or shape. Insome embodiments, particles that include a shape memory material can beselectively transitioned from a first state to a second state. Forexample, a heating device provided in the interior of a deliverycatheter can be used to cause a particle including a shape memorymaterial to transition from a first state to a second state. Shapememory materials and particles that include shape memory materials aredescribed in, for example, U.S. Patent Application Publication No. US2004/0091543 A1, published on May 13, 2004, and U.S. patent applicationSer. No. 10/791,103, filed Mar. 2, 2004, and entitled “EmbolicCompositions”, both of which are incorporated herein by reference.

As an additional example, in some embodiments, one or more of thematerials that flow through one or more of the orifices in a concentricnozzle can be a surface preferential material. Surface preferentialmaterials are described, for example, in U.S. patent application Ser.No. 10/791,552, filed on Mar. 2, 2004, and entitled “Embolization”,which is incorporated herein by reference.

As a further example, in certain embodiments, a particle can be coated(e.g., with a bioabsorbable material). For example, a particle can havean interior region including a radiopaque material, an exterior regionincluding a polymer, and a hydrogel coating over the exterior region.The coating can contain, for example, one or more therapeutic agents. Incertain embodiments, a particle can be coated to include a highconcentration of one or more therapeutic agents and/or one or more ofthe therapeutic agents can be loaded into the interior of the particle.The surface of the particle can release an initial dosage of therapeuticagent after which the body of the particle can provide a burst releaseof therapeutic agent. The therapeutic agent on the surface of theparticle can be the same as or different from the therapeutic agent inthe body of the particle. The therapeutic agent on the surface can beapplied by exposing the particle to a high concentration solution of thetherapeutic agent. The therapeutic agent coated particle can includeanother coating over the surface the therapeutic agent (e.g., adegradable and/or bioabsorbable polymer which erodes when the particleis administered). The coating can assist in controlling the rate atwhich therapeutic agent is released from the particle. For example, thecoating can be in the form of a porous membrane. The coating can delayan initial burst of therapeutic agent release. The coating can beapplied by dipping or spraying the particle. The erodible polymer can bea polysaccharide (such as an alginate). In some embodiments, the coatingcan be an inorganic, ionic salt. Other erodible coatings include watersoluble polymers (such as polyvinyl alcohol, e.g., that has not beencross-linked), biodegradable poly DL-lactide-poly ethylene glycol(PELA), hydrogels (e.g., polyacrylic acid, haluronic acid, gelatin,carboxymethyl cellulose), polyethylene glycols (PEG), chitosan,polyesters (e.g., polycaprolactones), and poly(lactic-co-glycolic) acids(e.g., poly(d-lactic-co-glycolic) acids). The coating can includetherapeutic agent or can be substantially free of therapeutic agent. Thetherapeutic agent in the coating can be the same as or different from anagent on a surface layer of the particle and/or within the particle. Apolymer coating, e.g. an erodible coating, can be applied to theparticle surface in embodiments in which a high concentration oftherapeutic agent has not been applied to the particle surface. Coatingsare described, for example, in U.S. Patent Application Publication No.US 2004/0076582 A1, published on Apr. 22, 2004, which is incorporatedherein by reference.

As an additional example, in certain embodiments, one or more of thematerials that flows through one or more of the orifices in a concentricnozzle can be bioerodible, such that the materials can eventually breakdown in the body and either be dispersed throughout the body or excretedfrom the body. A bioerodible material can be, for example, apolysaccharide (such as an alginate); a polysaccharide derivative; aninorganic, ionic salt; a water soluble polymer (such as a polyvinylalcohol, e.g., that has not been cross-linked); biodegradable polyDL-lactide-poly ethylene glycol (PELA); a hydrogel (e.g., polyacrylicacid, haluronic acid, gelatin, carboxymethyl cellulose); a polyethyleneglycol (PEG); chitosan; a polyester (e.g., a polycaprolactone); apoly(lactic-co-glycolic) acid (e.g., a poly(d-lactic-co-glycolic) acid);or a combination thereof.

As a further example, in some embodiments, a particle produced by aconcentric nozzle can include one of the following combinations ofmaterials: an interior region including a ferromagnetic material (e.g.,iron, an iron oxide (e.g., Fe₃O₄), magnetite, a ferrofluid) and anexterior region including a polymer (e.g., a polysaccharide); aninterior region including one type of therapeutic agent and an exteriorregion including a different type of therapeutic agent; or an interiorregion that includes a ferromagnetic material and an exterior regionthat includes a combination of a polymer and a gelling precursor.

As another example, in some embodiments the materials used in aconcentric nozzle to form particles can be selected based on theirimmiscibility, such that streams of the materials can remainsubstantially discrete as they flow through drop generator 1200. In suchembodiments, the streams can produce particles having an exterior regionof substantially one material and an interior region of substantiallyanother material.

As an additional example, in some embodiments, one or more of thesolutions that flows through one or more of the orifices in a concentricnozzle can be chilled prior to entering the concentric nozzle (e.g., toaffect the viscosity and/or flow rate of the solution).

As a further example, in certain embodiments, the materials that flowthrough a concentric nozzle can be selected to mix with each other uponcontact. For example, one material can be a ferromagnetic material,while the other material is polyvinyl alcohol.

As another example, while concentric nozzles have been described thathave two orifices, in some embodiments a concentric nozzle can includemore than two orifices (e.g., three orifices, four orifices, fiveorifices).

As an additional example, in certain embodiments, the orifices in aconcentric nozzle can be vertically spaced apart from each other. Forexample, FIG. 12 shows a concentric nozzle 700 that includes an innernozzle 710 concentrically disposed within an outer nozzle 720. Innernozzle 710 has an inner orifice 712, and outer nozzle 720 has an outerorifice 722. Inner orifice 712 is separated from outer orifice 722 by avertical distance “V”, which can be from about 0.5 millimeter to abouttwo millimeters (e.g., about one millimeter). In some embodiments,vertical displacement of the orifices of a concentric nozzle can enhancemixing of the solutions flowing through the nozzle prior to the point atwhich the solutions contact the gelling agent. In such embodiments,drops formed by the nozzle can include a mixture of the solutions. Incertain embodiments, mixing of the solutions within the concentricnozzle can be enhanced by starting to flow one of the solutions throughthe outer nozzle of the concentric nozzle prior to starting to flow theother solution through the inner nozzle of the concentric nozzle.

As another example, in some embodiments, the particles can bemechanically shaped during or after the particle formation process to benonspherical (e.g., ellipsoidal). In certain embodiments, one or moreparticles can be shaped (e.g., molded, compressed, punched, and/oragglomerated with other particles) at different points in the particlemanufacturing process. In some embodiments (e.g., where the polymer is apolyvinyl alcohol and the gelling precursor is sodium alginate), aftercontacting the particles with the gelling agent but beforecross-linking, the particles can be physically deformed into a specificshape and/or size. After shaping, the polymer (e.g., polyvinyl alcohol)can be cross-linked, optionally followed by substantial removal of thegelling precursor (e.g., alginate). While substantially sphericalparticles are preferred, non-spherical particles can be manufactured andformed by controlling, for example, drop formation conditions. In someembodiments, nonspherical particles can be formed by post-processing theparticles (e.g., by cutting or dicing into other shapes). Particleshaping is described, for example, in co-pending U.S. Patent ApplicationPublication No. US 2003/0203985 A1, published on Oct. 30, 2003, which isincorporated herein by reference.

As a further example, in some embodiments, particles having differentshapes, sizes, physical properties, and/or chemical properties, can beused together in an embolization procedure. The different particles canbe delivered into the body of a subject in a predetermined sequence orsimultaneously. In certain embodiments, mixtures of different particlescan be delivered using a multi-lumen catheter and/or syringe. In someembodiments, particles having different shapes and/or sizes can becapable of interacting synergistically (e.g., by engaging orinterlocking) to form a well-packed occlusion, thereby enhancingembolization. Particles with different shapes, sizes, physicalproperties, and/or chemical properties, and methods of embolizationusing such particles are described, for example, in U.S. PatentApplication Publication No. US 2004/0091543 A1, published on May 13,2004, and in U.S. patent application Ser. No. 10/791,103, filed Mar. 2,2004, and entitled “Embolic Compositions”, both of which areincorporated herein by reference.

As an additional example, in some embodiments the particles can be usedfor tissue bulking. As an example, the particles can be placed (e.g.,injected) into tissue adjacent to a body passageway. The particles cannarrow the passageway, thereby providing bulk and allowing the tissue toconstrict the passageway more easily. The particles can be placed in thetissue according to a number of different methods, for example,percutaneously, laparoscopically, and/or through a catheter. In certainembodiments, a cavity can be formed in the tissue, and the particles canbe placed in the cavity. Particle tissue bulking can be used to treat,for example, intrinsic sphincteric deficiency (ISD), vesicoureteralreflux, gastroesophageal reflux disease (GERD), and/or vocal cordparalysis (e.g., to restore glottic competence in cases of paralyticdysphonia). In some embodiments, particle tissue bulking can be used totreat urinary incontinence and/or fecal incontinence. The particles canbe used as a graft material or a filler to fill and/or to smooth outsoft tissue defects, such as for reconstructive or cosmetic applications(e.g., surgery). Examples of soft tissue defect applications includecleft lips, scars (e.g., depressed scars from chicken pox or acnescars), indentations resulting from liposuction, wrinkles (e.g.,glabella frown wrinkles), and soft tissue augmentation of thin lips.Tissue bulking is described, for example, in co-pending U.S. PatentApplication Publication No. US 2003/0233150 A1, published on Dec. 18,2003, which is incorporated herein by reference.

As a further example, in some embodiments a particle can be porousand/or can include one or more cavities. In certain embodiments, theparticle can have a substantially uniform pore structure. In someembodiments, the particle can have a non-uniform pore structure. Forexample, the particle can have a substantially non-porous interiorregion (e.g., formed of a polyvinyl alcohol) and a porous exteriorregion (e.g., formed of a mixture of a polyvinyl alcohol and alginate).Porous particles are described in U.S. Published Patent Application No.US 2004/0096662 A1, published on May 20, 2004, which is incorporatedherein by reference.

As another example, in some embodiments a solution can be added to theconcentric nozzle to enhance the porosity of particles produced by theconcentric nozzle. Examples of porosity-enhancing solutions includestarch, sodium chloride at a relatively high concentration (e.g., morethan about 0.9 percent, from about one percent to about five percent,from about one percent to about two percent), and calcium chloride(e.g., at a concentration of at least about 50 mM). For example, calciumchloride can be added to a sodium alginate gelling precursor solution toincrease the porosity of the particles produced from the solution.

As an additional example, in certain embodiments, the particles that areproduced by a concentric nozzle can be linked together to form particlechains. For example, the particles can be connected to each other bylinks that are formed of one or more of the same material(s) as theparticles, or of one or more different material(s) from the particles.Alternatively or additionally, the concentric nozzle can be used to formparticle chains. For example, the vibration frequency of the concentricnozzle can be selected to cause the concentric nozzle to form particlechains. Particle chains and methods of making particle chains aredescribed, for example, in U.S. patent application Ser. No. 10/830,195,filed on Apr. 22, 2004, and entitled “Embolization”, which isincorporated herein by reference.

Other embodiments are in the claims.

1-43. (canceled)
 44. A method of making particles, the methodcomprising: flowing a first material through a first orifice defined bya nozzle to form a first stream comprising the first fluid; flowing asecond material through a second orifice defined by the nozzle to form asecond stream comprising the second fluid; combining the first andsecond streams; exposing the combined first and second streams to aperiodic disturbance to form drops comprising the first and secondmaterials; and forming particles from the drops, the particlescomprising the first and second materials.
 45. The method of claim 44,wherein the particles have an arithmetic mean diameter of from about tenmicrons to about 3,000 microns.
 46. The method of claim 44, wherein thefirst orifice has a diameter of from about 50 microns to about 1,000microns.
 47. The method of claim 44, wherein the first orifice has adiameter of from about 50 microns to about 300 microns.
 48. The methodof claim 44, wherein the second orifice has a diameter of from about 50microns to about 1,000 microns.
 49. The method of claim 44, wherein thefirst orifice has a first diameter, the second orifice has a seconddiameter, and the difference between the first and second diameters isat least about 50 microns.
 50. The method of claim 44, wherein the firstorifice is disposed within the second orifice.
 51. The method of claim50, wherein the first orifice and the second orifice are concentric. 52.The method of claim 51, wherein the first orifice is disposed at avertical distance of about one millimeter from the second orifice. 53.The method of claim 44, wherein the first material flows through thefirst orifice at a rate of from about two milliliters per minute toabout ten milliliters per minute.
 54. The method of claim 53, whereinthe second material flows through the second orifice at a rate of fromabout two milliliters per minute to about 20 milliliters per minute. 55.The method of claim 44, wherein the first material comprises a polymer.56. The method of claim 55, wherein the second material comprises agelling precursor.
 57. The method of claim 56, wherein forming theparticles includes converting the gelling precursor from a solution intoa gel, and the method further comprises removing at least some of thegel from the particles.
 58. The method of claim 44, wherein the firstmaterial and the second material are immiscible.
 59. The method of claim44, wherein the first stream and the second stream are concentric. 60.The method of claim 44, wherein the first material forms an interiorregion of the drops and the second material forms a surface region ofthe drops.
 61. The method of claim 44, wherein a viscosity of the firstmaterial is greater than a viscosity of the second material.
 62. Themethod of claim 44, wherein a viscosity of the second material isgreater than a viscosity of the first material.
 63. The method of claim44, wherein the particles contain pores.
 64. The method of claim 63,wherein the particles have a first density of pores in an interiorregion and a second density of pores at a surface region, the firstdensity being different from the second density.
 65. The method of claim64, wherein the first density is greater than the second density. 66.The method of claim 63, wherein the particles have a first average poresize in an interior region and a second average pore size at a surfaceregion, the first average pore size being different from the secondaverage pore size.
 67. The method of claim 66, wherein the first averagepore size is greater than the second average pore size.
 68. The methodof claim 44, wherein the particles are substantially non-porous.
 69. Themethod of claim 44, wherein the periodic disturbance is provided byvibrating the plurality of streams.
 70. The method of claim 44, whereinforming the drops includes establishing an electrostatic potentialbetween the first and second streams and a vessel configured to receivethe drops.
 71. A method of making particles, the method comprising:flowing a polymer through a first orifice defined by a nozzle to form afirst stream comprising the first fluid; flowing a gelling precursorthrough a second orifice defined by the nozzle to form a second streamcomprising the second fluid; combining the first and second streams;exposing the combined first and second streams to a periodic disturbanceto form drops comprising the polymer and the gelling precursor; andcontacting the drops with a gelling agent to convert the gellingprecursor to a gel, thereby providing particles comprising the polymerand the gel.
 72. The method of claim 71, wherein the particles have anarithmetic mean diameter of from about ten microns to about 3,000microns.
 73. The method of claim 71, wherein the polymer comprisespolyvinyl alcohol.
 74. The method of claim 71, further comprisingcross-linking the polymer contained in the particles.
 75. The method ofclaim 74, further comprising, after cross-linking the polymer containedin the particles, removing the gel from the particles.
 76. The method ofclaim 75, wherein the polymer comprises polyvinyl alcohol.
 77. A methodof making particles, the method comprising: flowing polyvinyl alcoholthrough a first orifice defined by a nozzle to form a first streamcomprising the first fluid; flowing a gelling precursor through a secondorifice defined by the nozzle to form a second stream comprising thesecond fluid; combining the first and second streams; exposing thecombined first and second streams to a periodic disturbance to formdrops comprising the polyvinyl alcohol and the gelling precursor;contacting the drops with a gelling agent to convert the gellingprecursor to a gel and form particles comprising the polyvinyl alcoholand the gel; cross-linking the polyvinyl alcohol in the particles;removing the gel from the particles to provide particles having pores,wherein the particles having pores have an arithmetic mean diameter offrom about ten microns to about 3,000 microns.